tbuckley/cabot-search huggingface dataset:
Genomic biomarker for the top risk factor of gallbladder cancer, cholelithiasis, in a Latinx population.
Authors: Ping Yang
Journal: Journal of Clinical Oncology (2023)

e16326 Background: Cholelithiasis or Gallstone disease (GSD), is one of the most common and costly digestive disorders in adults worldwide, presenting 10-20% of the general population but in greater than 30% of Latina and Hispanic American women aged 40 years or older. Moreover, GSD individuals contribute significantly to the incidence and mortality of gallbladder and other digestive system cancers; specifically, the excessive risk of gallbladder cancer is 3-10-fold. Parallel to gallbladder cancer, an appalling female preponderance of GSD has been documented for decades; thus, precisely defining high-risk populations and properly managing patients with GSD would lead to reduced disease burden from GSD and multiple cancers. Several genome-wide association studies (GWAS) in the past have identified genes associated with GSD but few were focused on Latinx population. Methods: To identify genetic risk factors for GSD in Latinx population, we used the Sangre Por Salud cohort (SPS) where participants are Latinx adult individuals aged 18-85 years who were current patients in the Mountain Park Health Center in Arizona. This sample represents historically underrepresented population with low socioeconomic status that are primarily Spanish-speaking, majority being born outside of the US, with low rates of health insurance coverage. A total of 172 GSD cases were identified, each matched with 6 controls (n = 1032) who were people from the same community but without history of GSD diagnosis; matching variables are age at enrollment to SPS, sex, height and weight, dyslipidemia, and HbA1C level indicative of type 2 diabetes. We characterized genome-wide interrogation for biomarkers predicting GSD and contributing to the observed gender disparity by performing a GWAS using a matched case-control design. Results: We identified several novel loci associated with GSD and validated few loci that were reported in previous GWAS. The top 3 loci (MATN2, GPRIN3, GPC6) were strongly associated with GSD in our overall analysis; follow-up pathway enrichment analysis suggests enrichment of GO terms that are associated with immunological pathways, enzymatic processes in gallbladder, liver and gastrointestinal tract and GSD pathology. In a sex-specific analysis, CDHR3 and RPL31P35-SEC61G were identified for females, which have been associated respectively with rhinovirus C infection and HbA1c level in previous studies. Conclusions: Our findings suggest directions towards better and deeper understanding of sex differences in GSD pathology, biological mechanisms, and disease progression among Latinx people. Knowing approximately 80% of gallbladder cancer patients harbored gallstones, our optimal goal is to provide evidence for an innovative strategy to early detect and effectively intervene the modifiable risk factors to reduce gallbladder cancer burden in high risk populations.
Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study.
Authors: Jian Jennifer Chen, Melanie Vincent, David M. Peereboom, Randolph Watnick, Susanne Fyfe, Wendy Li, Suming Wang, James Mahoney, Michael Cieslewicz, Jing Watnick
Journal: Journal of Clinical Oncology (2023)

2021 Background: The cyclic peptide VT1021 is a first-in-class therapeutic agent that has been shown to inhibit tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprogramming the immune tumor microenvironment (TME) in preclinical models. Subsequently, VT1021 has been tested in a phase I/II clinical study in solid tumors (NCT03364400) and has advanced to a phase II/III clinical study in glioblastoma (NCT03970447). VT1021 has demonstrated promising single-agent clinical activity against recurrent glioblastoma (rGBM) in a phase I/II expansion study. Among 22 evaluable subjects with rGBM, 3 had complete response (CR), 1 had partial response (PR), and 6 had stable disease (SD) with an average study duration of over 120 days. One subject has been on VT1021 treatment for &gt; 900 days with no measurable lesion left. The overall disease control rate (DCR) was 45%. Here, we sought to examine the peripheral immune cell profile(s) in response to VT1021 and explore the association between these profiles and clinical responses in rGBM subjects. Methods: In the phase I/II expansion study, 22 evaluable rGBM subjects received VT1021 at a dose of 11.8 mg/kg (twice per week intravenously) until disease progression. Peripheral blood samples were collected from all evaluable subjects; immune cell profiles were analyzed by flow cytometry. Results: The immune profiles following VT1021 treatment on day 1 did not vary significantly among rGBM subjects, regardless of response. Intriguingly, after long-term VT1021 treatment (day 53), our analysis of the immune profiles revealed beneficial and sustained changes in three cytotoxic T Cell (CTL) parameters and PD-L1 + MDSCs that correlated with response. Specifically, CR/PR subjects showed a 20% increase in total CTLs (Pre 33.79% vs. 6hr 40.42%), a 66% increase in proliferating CTLs (Pre 1.37% vs. 6hr 2.28%) and a 63% increase in CTL/Treg ratio (Pre 7.85 vs. 6hr 12.81) on day 53 of VT1021 treatment. In contrast, SD and PD subjects exhibited no change or decrease in these three CTL parameters, respectively. We also observed that CR/PR subjects experienced a sustained decrease in PD-L1 + MDSCs after VT1021 treatment (day 1 Pre 95.96% vs. day 53 Pre 92.66% and day 53 6hr 88.06%). Conversely, the sustained decrease of PD-L1 + MDSCs after VT1021 treatment was not observed in SD and PD subjects. Conclusions: Here we report that the durable responses of peripheral immune cells to VT1021 may be associated with better clinical outcomes in rGBM subjects. These findings are consistent with the MOA of TSP-1 to reprogram the TME by stimulating immune and inflammatory cell functions. While the interpretation of our data is limited by the lack of a control arm and the small sample size, the results provide a signal and warrant continued analysis of these parameters in the ongoing phase II/III trial.
A phase IV study to evaluate the safety of fruquintinib in Chinese real-world clinical practice.
Authors: Jin Li, Zhi-Qiang Wang, Haijun Zhong, Yifu He, Chen Zhang, Zuoxing Niu, Shujun Yang, Tao Zhang, Liangjun Zhu, Yongqian Shu, Jianjun Peng, Yan Song, Jian Li, Ying Yuan, Haibo Zhang, Gengsheng Yu, yun-Qi Hua, Jianjun Xiao, Michael Shi, Weiguo Su
Journal: Journal of Clinical Oncology (2023)

e15568 Background: Fruquintinib is a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, which was approved in China for 3L mCRC patients based on results of FRESCO study (NCT02314819). In addition, FRESCO-2 (NCT04322539) demonstrated a consistent efficacy and safety profile of Fruquintinib in more heavily treated mCRC worldwide patients. This Phase IV study aims to evaluate the safety of Fruquintinib in real-world clinical practice in China. Methods: This is a prospective, multicenter, phase IV study, to evaluate a real-world safety of Fruquintinib in China. Patients who are within the first cycle of Fruquintinib treatment or plan to use Fruquintinib within 1 week can be enrolled into this study. Three visits are scheduled, including the day of consent, 1 month after consent, and 6 months after consent or 30 days after the last dose (whichever occurs first). The primary endpoint is the collected AE. Results: From April 2019 to Feb 2022, a total of 3005 patients from 96 study sites received at least one dose of fruquintinib and were enrolled in the safety analysis set (SS). The median age of the patients was 60, of which 1053 patients (35.0%) were ≥65.In SS, a total of 1923 patients (64.0%) started Fruquintinib at 5 mg/day. The median relative dose intensity was 85.3%; the median exposure time was 2.7months. In SS, 2291 patients (76.2%) reported TEAEs; 1901 patients (63.3%) reported investigator assessed fruquintinib-related TEAEs.718 patients (23.9%) reported ≥Grade3 TEAEs; 418 patients (13.9%) reported investigator assessed fruquintinib-related ≥Grade3 TEAEs. 330 patients (11.0%) reported SAE; 86 patients (2.9%) reported investigator assessed fruquintinib-related SAE. 169 patients (5.6 %) reported TEAEs leading to death;8 patients (0.3%) reported investigator assessed fruquintinib-related TEAEs leading to death. The most frequent fruquintinib-related TEAEs(＞10%）include palmar-plantar erythrodysesthesia syndrome (PPES,19.4%)，hypertension (15.6%) &amp; fatigue (10.1%); the most frequent Fruquintinib-related≥Grade 3 TEAE (≥1%）include hypertension (6.4%) &amp; PPES (2.2%); The most frequent fruquintinib-related TEAE (≥5%) leading to dose modification was PPES (5.4%). Conclusions: The results are consistent with the fruquintinib safety profile observed in existing clinical studies. No new or significant safety signals were identified. Clinical trial information: NCT04005066 .
Combination beta-adrenergic blockade and immunotherapy for the treatment of primary and metastatic brain cancer.
Authors: Selena Lorrey, Lucas P Wachsmuth, Quinn T Ostrom, Peter E. Fecci
Journal: Journal of Clinical Oncology (2023)

e14017 Background: Brain tumors present a unique challenge to immunotherapeutic success, as immune responses in patients with brain tumors are suppressed both within the tumor microenvironment and peripherally. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with primary brain tumors like glioblastoma, represent a population in dire need of more thoughtful, targeted treatment approaches. Through this work we present an immunosuppressive axis specifically activated in the context of intracranial malignancies that inhibits immunotherapeutic success in these patients. We demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. More specifically, beta-adrenergic signaling is known to suppress immune responses in various contexts. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Methods: Using the SEER Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. Results: We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a highly-prescribed FDA-approved beta-blocker, extended survival. Conclusions: Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.
A multicenter, single-arm phase 2 study of surufatinib plus toripalimab for patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer.
Authors: Dongmei Ji, Lijie Song, Ying Cheng, Weina Shen, Muyu Kuang, Jiaying Chen, Minjie Yang, Hongxia Cui, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Songhua Fan, Michael Shi, Weiguo Su, Qinghai Ji
Journal: Journal of Clinical Oncology (2023)

6089 Background: For patients (pts) with radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC), there presents a considerable therapeutic challenge with poor long-term outcomes. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) in combination with toripalimab (an anti-PD-1 antibody) in pts with RAIR-DTC. Methods: Eligible pts were with locally advanced or metastatic RAIR-DTC who were not amenable for surgery or external beam radiotherapy, with a radiologically confirmed disease progression within 12 months before treatment, and with ≥6 months since last radioiodine treatment. Enrolled pts received surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From March 2020 to November 2021, 15 pts were enrolled and received a median duration of 11.1 months of the combination treatment, with a median age of 61 years (range: 37-74). 9 (60%) pts were male, and 12 (80%) had papillary thyroid cancer. Of the 13 pts with PD-L1 immunochemical results, 6 pts had PD-L1 CPS ≥1%. As of 28 Dec 2022, the median follow-up duration was 22.11 months. Of the 15 pts with at least one post-baseline tumor assessment, the confirmed ORR was 33.3% (5 PRs) and DCR was 93.3%. mDoR was 8.34 months. mPFS (95%CI) was 10.91 months (4.01, NA). mOS was not reached, and 12-month OS rate was 100%. 14 (93.3%) pts had treatment-emergent adverse events (TEAEs), and 10 (66.7%) pts reported grade ≥3 TEAEs, most commonly (≥10% pts) with hypocalcemia (20%), diarrhea (20%) and hypertension (13%). There was no death due to TEAE in the study. Conclusions: Surufatinib plus toripalimab showed encouraging antitumor activity and tolerable safety profile in pts with locally advanced or metastatic RAIR-DTC. Clinical trial information: NCT04169672 .
Comparison of next-generation sequencing and flow cytometry in detecting minimal residual disease in adult acute lymphoid leukemia: Evaluating clinical outcomes in a single-center study.
Authors: Vinay Nittur, Karam Ashouri, Blake Adnani, Jennifer Hwang, Denaly Chen, Kimberly Schiff, Lakshmi Savitala-Damerla, Abdullah Ladha, Karrune Woan, Eric Leon Tam, Preet Chaudhary, George Yaghmour
Journal: Journal of Clinical Oncology (2023)

7033 Background: Detection of measurable residual disease (MRD) is an important biomarker to direct treatment for adult patients with acute lymphoblastic leukemia (ALL). Currently, multiparameter flow cytometry (MFC) is standard of care and can detect residual leukemia cells in 1 out of 100,000 cells (1 × 10−5). Routine use of next-generation sequencing (NGS) assays with higher levels of sensitivity may improve disease-free survival and overall survival in adult ALL patients. The clonoSEQ MRD assay (Adaptive Biotechnologies Corporation, USA) can detect MRD at a sensitivity of 1 × 10−6 . In this study, we compare the detection of MRD by clonoSEQ assay and MFC in adult ALL patients at a single institution. Methods: We performed a retrospective study evaluating 92 adult patients with B- or T-ALL admitted to Norris Comprehensive Cancer Center between 2014 and 2022. Patients were excluded if they did not achieve complete remission (N=9) or if they presented with prior relapse (N=27). Median time to first complete remission (CR1) was 2.38 months. Among our cohort (N=56 patients), all patients underwent pre-treatment bone marrow sampling which was used for Clonoseq assay. 52 patients had contemporaneous MFC which was used for comparative analysis. MRD on MFC was defined as residual leukemia cells at a sensitivity of 1 × 10−5. MRD on Clonoseq assay was evaluated at 1 × 10−6; residual cells under this limit were considered MRD−. Results: Demographics are summarized in the table. Median time to follow-up from MRD assessment was 18.0 months. 10 patients relapsed (17.9%), 3 patients died (5.4%), and 20 patients (35.7%) underwent allogeneic transplant during first remission. Among 52 patients analyzed by both MFC and NGS at CR, 26 (50%) were concordantly MRD− by NGS and NGF, 13 (25%) were discordantly MRD− by NGF but MRD+ by NGS, and 13 (25%) concordantly MRD+ by NGS and NGF. Residual cell levels between NGS and NGF were strongly correlated (R-Squared = 0.6744, p&lt;0.001), however, MRD status was significantly different between NGS and NGF (p&lt;0.001 using Fisher’s Exact Test). This difference was likely driven by disparities in the limits of detection between both methods. Conclusions: Assessment of MRD using the clonoSEQ assay over a standard MFC-based approach adds crucial prognostic information among adult ALL patients who achieved CR. [Table: see text]
Outcomes of renal function and efficacy in patients with muscle invasive bladder cancer treated by tislelizumab-based immunochemotherapy.
Authors: Hong Zheng Li, Yuanjie Niu, Hailong Hu, Zesheng An, Chong Shen, Zhouliang Wu, Yunkai Qie, Houyuan Chen, Gangjian Zhao, Shiwang Huang, Yiduo Bai, Shizheng Guo, Peng Li, Yuda Lin
Journal: Journal of Clinical Oncology (2023)

e16608 Background: The occurrence PD-1 ICIs brings a new era of treatment for bladder cancer (BC). Although the safety and efficacy of most PD-1 ICIs have been certified progressively, whether they can be used in patients (pts) with renal impairment is always a concern for clinicians. Consequently, we intend to investigate the variation of renal function and efficacy of PD-1 ICIs based immunochemotherapy for pts with muscle invasive bladder cancer (MIBC) and renal insufficiency in short term. Methods: Our study relied on population of the TRUCE-01 trial (NCT04730219), an open-label, single-arm phase II study of tislelizumab based immunochemotherapy in pts with MIBC. Data of pts, including demographic information, imaging and pathological assessment of efficacy, and serum creatinine (SCr) level in baseline, after the first, second and third cycle (C1, C2 and C3) of treatment was collected and analyzed retrospectively. We calculated at estimated glomerular filtration rate (eGFR) according to CKD-EPI formula 2009, and divided pts into different groups according to baseline eGFR, in reference to CKD categories in the K-DIGO 2012 guidelines. Results: 74 pts have been included in our research in total. The median age was 69.5 years (IQR 61.7-75.0) and 56 (75.7%) were male. Median SCr in baseline was 77.4umol/L (IQR 67.8-96.6), while median eGFR was 84.6 (IQR 63.6-94.0) (the unit of eGFR is mL/min/1.73 m 2 ). At baseline, 25 pts were classified as G1 (eGFR≥90), 36 as G2(eGFR &lt;90 and≥60), 12 as G3 (eGFR &lt;60 and ≥30), and 1 as G4 (eGFR &lt;30 and≥15). No significant difference was found in eGFR between pts with CKD G1-2 in comparison to baseline and after C1, C2, C3 of treatment (All p&gt;0.05). In pts with CKD G3-4, it is notable that eGFR may improve when the C1, C2 and C3 completed, in comparison to the baseline (p=0.087, p=0.046, p=0.114 in Wilcoxson test, p=0.082 in Repeated Measures ANOVA). 48 (64.9%) pts received 3 cycles of ICIs and underwent an operation. 24 of 48 (50%) pts received radical cystectomy (RC) and others were treated by maximal TURBT. All of them have conducted efficacy evaluation by both radiographic test and pathology. It is noted that no statistical difference in outcomes between Group G1-2 and G3-4 (p=0.772). Conclusions: Despite renal impairment is common in pts with MIBC, PD-1 immunotherapy is generally safe for kidney of MIBC patients with renal insufficiency and have no influence on efficacy in the short term. The potential improvement in eGFR of patients with worse renal function and its mechanism is essential to be revealed and verified. [Table: see text]
The impact of COVID-19 on national trends of hospitalization and outcomes for acute leukemias.
Authors: Prarthna V. Bhardwaj, Sneha Nagesh Rao, Deepak Pasupula, Kathan Mehta, Sudeep Kumar Siddappa Malleshappa
Journal: Journal of Clinical Oncology (2023)

e18869 Background: Acute leukemias are traditionally managed in a hospital setting. During the initial phase of the COVID-19 pandemic, there was a gross shortage of hospital resources and rationing of care. We aimed to study the differences in national trends of hospitalizations and outcomes for acute leukemias in 2019 (pre-pandemic) and 2020 across the United States. Methods: We performed a retrospective study utilizing the National Inpatient Sample (NIS) of adults hospitalized for management of acute leukemias as the primary diagnosis using ICD-10-CM codes. We excluded all patients with a prior or current hospitalization for stem cell transplantation. We compared the outcomes between patients presenting in 2019 (pre-pandemic) and 2020. Outcomes included mortality, length of stay (LOS) and cost of hospitalization. We compared mortality among patients with and without COVID in 2020 using chi-square analysis. Results: Of 166795 admissions for acute leukemia, 71.8% were acute myeloid leukemia (AML), 25.2% were acute lymphoblastic leukemia (ALL) and 3.1% were acute promyelocytic leukemia (APML). Overall, patients were predominantly male (55%), White (68%) presenting to large hospitals (67%) specifically urban teaching hospitals (88%). When compared between 2019 and 2020, there was no difference in the proportion not receiving chemotherapy for their leukemia (77.7% vs 78.6% in 2019 and 2020 respectively). There were no differences between mortality (8.6% vs 8.7%) or median LOS (6 days vs 5 days). The total cost of hospitalization was higher in 2020 ($155,961) compared to 2019 ($151,372). When stratified by COVID-19 infection in 2020, mortality was higher among COVID infected patients in AML (27.5% vs 10.08%, p=0.000), in ALL (16.87% vs 3.30%, p=0.000) as well as APML (26.32% vs 11.5%, p=0.139). Conclusions: Overall, there were no differences in the hospitalizations, rates of chemotherapy administration, mortality or LOS for acute leukemia pre and post COVID-19. However, in 2020, patients with AML and ALL with a concurrent COVID-19 diagnosis had a higher mortality. [Table: see text]